Serotonin, acting as a chemical neurotransmitter in the central nervous system (CNS), is importantly implicated in a variety of human neuro- and psychopathologies. However, its basic neurobiological role remains somewhat obscure. A true appreciation of how serotonin functions in disease processes, and treatment of them, presupposes an understanding of its actions in normal mammalian physiology and behavior. To that end, the present research is aimed at furthering knowledge of the basic functioning of the CNS serotonin system primarily through recording the electrical activity of brain serotonin neurons in behaving animals. Recordings will be made in both the rostral/ascending group of serotonin neurons (in the dorsal raphe nucleus) as well as the caudal/descending group (in the nuclei raphe obscurus and pallidus). The proposed studies are an outgrowth of our basic hypothesis that the activity of serotonin neurons is closely linked to level of behavioral activation/tonic motor activity, and especially to repetitive motor activity (central pattern generator-mediated). Two major groups of experiments are proposed: 1) environmental and behavioral factors that may modulate the basic activity of these brain cells, and the neurochemicals that mediate these effects; 2) the role of brain serotonin neurons in central fatigue. The importance of this latter issue derives from the fact that fatigue is considered an important component in a number of disease processes (e.g., chronic fatigue syndrome, multiple sclerosis, and depression). In addition to single unit recordings in behaving animals, the experiments will employ: 1) In vivo microdialysis measures of brain serotonin and dopamine; 2) Local drug administration by means of reverse microdialysis; 3) c-Fos expression (in conjunction with double labeling) as an indicator of serotonin neurons activated under specific conditions; and 4) Computer-generated spike train analyses.